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145 Cards in this Set
- Front
- Back
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When did Jenner innoculate the kid with cowpox
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1796
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When did Pasteur invent the Rabies vaccine
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1880s
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What is the difference between passive and active immunization
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passive immunization involves inoculation with the products of an immune response aka adaptive transfer. It is only effective for the duration of that product. An example of passive immunization is the transfer of maternal IgG to a baby via breastmilk. Active immunization involves inoculation with a form of virus to stimulate an immune repsonse and memory
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What are the three "considerations" of a vaccine
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1. effectivness 2. saftey 3. manufacture/ distribution
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Describe an effective vaccine
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1. must induce a protective immune response preferably antibody and cell mediated 2. The protection should be strong and long term 3. Must work for the majority of the population
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Describe herd immunity
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If the majority of the population is immunized the virus can be erradicated because there are few suceptible hosts. The necessary percentage varies by virus and host.
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What viral components must not be in a vaccine to ensure saftey
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1. nucleic acids should not be present in viral protein vaccines 2. no infectious virions in inactivated vaccines 3. no contaminating agents 4. side effects must not be worse than virus infection
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What are three areas of concern for viral vaccine manufacturing
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1. must be stable 2. must be easy to administer 3. low cost
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In which two ways must vaccines be stable?
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1. biologically- no enetic revertants 2. physically- cold storage requirements
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What are the advantages and disadvantages of an inacticated vaccine
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advantages- safe, easy to store disadvantages- immune response not as strong compared to live attenuated
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What are the advantages and disadvantages of a live attenuated vaccine
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advantages- yields both innate and adpative immune response, highly immunogenic disadvantages- may still cause come disease, revertants
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Describe a virus like particle vaccine. What are the advantages and disadvantages of using this type of vaccine?
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VLP vaccine uses purified, empty virus capsids. The virions self assemble from recombinant structural proteins. The virions do not contain nucleic acid. The advantages are that the particles are non-infections and they retain most of the surface epitopes. The disadvantages are that they are not applicable for all viruses and they require booster shots.
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Describe a subunit vaccine. What are the advantages and disadvantages of using this type of vaccine?
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A subunit vaccine uses purified virus components or synthetic peptides. + safe, - weak immune response
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Describe a DNA vaccine. What are the advantages and disadvantages of using this type of vaccine?
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A DNA vaccine uses a DNA plasmid with a viral gene and a host promoter. +safe and very little DNA necessary - weak immune response
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Describe a live attenuated viral vector and foreign gene expression vaccine.
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This vaccine uses a non-pathogenic virus to express a protein from a pthogenic virus
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Briefly describe the history of the trivalent polio vaccine
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1955- Salk introduces inactivated vaccine, 1962 Sabin introduces attenuated vaccine 1988 global polio eradication efforts begin, 1990s Sabin vaccine revertants detected, as of 2006 polio still endemicin Indai, Pakistan, Nigeria, and Afganistan
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When was the first flu vaccine introduced
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1944, inactivated
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Describe the contents of the seasonal flu vaccin
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seasonal vaccines are made against 3 strais (a trivalent vaccine) it can be given as an inactivcated injection or as a attenuated nasal spray
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Describe the gardasil vaccine
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Quadrivalent, protects against HPV 16, 18, 11, and 6. approved for females and males agest 9-26, given as 3 injections over a 6 month period
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What are some challenges associated with the gardasil vaccine
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Public acceptance- stigma associated with STIs, side effects Cost
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List some challgens to developing a vaccine for viruses like dengue or rhinovirus
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high mutation rate, integration into host genome, infection of immunologically protected region, virus targets immune system, multiple serotypes, cost and time invovled in developing the vaccine
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What family does influencza belong two? Describe it's basic viral properties
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Family = Orthomyxoviridae, enveloped, single stranded negative sense fragmented RNA genome
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Describe the nomenclature of the influenza virus A/PR/8/34(H1N1)
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A/PR/8/34(H1N1)= Type/place first isolated/strain number/year isolated/type of hemagglutinin and neruaminidase
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Where does the influenza virus replicate? What consequence does this have for drug therapy?
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Influenza is unusual for an RNA virus in that it replicates in the nucleus. This means that drugs that block host cell mRNA synthesis will also block influenza virus
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What is unique about the way in which influenza aquires its 5' caps
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It steals preformed caps from host cell mRNAs
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What symptom can help differntiate the flu from the common cold
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rhinorrhea is not promiment with the flu
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How can influenza associated pneumonia be differentiated from bacterial?
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No lobar consolidation on chest x-ray
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Describe the bacterial pneumonia secondary to influenza
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Classic influenza with improvement followed by fever, cough, spumtum production and lung consolidation, often S. pneumonia, S. aureus, H. influenzae, more common in elderly/ lung disease
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What is the differenc between antigenic shift and antigenic drift of the flu virus?
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antigenic shift involves a reassortment event that introduces a new gene segment into a circulating human strain, drift consists of point mutatios in currently circulating strains that alter the virulence slightly or reduce the effectivenss of immne protection
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What type of immune response is the predominately protective response to influenzae
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antibody to the HA, 15 variations of HA 3 of which are human
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Describe influenza reassortment
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infection of the same cell with two different strains results in random packaging of genome segments, one or more genes can be transferred between strains leading to new properties
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Influenza is mainly a brid virus, how does this explain how new pandemics arise?
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Influenza is mainly a brid virus, how does this explain how new pandemics arise? Pandemic reassortment results in new bird HA jumping into human background strain
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What is a mixing vessel
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A species that is permissive for replication of both human and avian flu viruses. Pigs can be infected with both strains depending on receptor specificity (avain strains use A2-3 linked sialic acid, humnas use 2,6, pigs have both)
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What agricultural practice may result in pandemic flu strains
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Most pandmic strains have arisen in southeast asia where it is common to raise pigs and ducks on the same farm. The pigs are fed duck feces which contain flu virus (avian flu is an enteric infection and is shed in high amounts in the feces)
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Describe the unusual infection pattern of the 1918 flu epidemic
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A first wave that was less virulent occurred in june and july, an abnormal time of year for the flu. This was follwed by a highly lethal wave in novemenber and a third wave in the winter of 1919. The pattern was novel and occurred at a scale not previously seen
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Describe the severity of the 1918 flu pandemic
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1/3 of world popluation infected, 50 million deaths, rapidly fatal
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Describe the unusual death curve of the 1918 flu pandemic
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unusual target population, a spike in deaths among young adults in addition to the very young and very old
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Describe signifcant change in the way avian flu infects humans that occurred in 1998
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prior to 1998 bird flu strains could not directly infect humans. In 1998 H5 avain strain jumped directly to humans in Hong Kong with a mortality rate of 60% Luckly the infection involed direct contact with patents or dead birds so transmission was poor. Additional strains have also made the jump. Right now it isn't that big of a problem because transmission is poor but if this changes we're screwed because it's very deadly, we have no vaccine, and the avain strains are drug resistant
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What factors generated so much concern over the 2009 H1N1 outbreak
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similarities to 1918 outbreak (occurred in spring, similar properties, HA gene similar, mortality rate high in young adutls, rapidly fatal)
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List the two targest of influenza antivirals and give examples of drugs that do this
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1. M2 ion channel inhibitors- Amantidine, Rimantidine, 2. Neuraminidase blockers- Tamiflu, Relenza
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Briefly describe how the influenza vaccine is made
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each new strain identified to cause an epidemic is isolated, reassortment is used to transfer the new HA into the standard human vaccine strain, the vaccine strain is prepared in large amounts in chicken eggs then purified, inactivated, tested, and apporved. This process can take 9-12 months
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What two disease can hepatitis C virus cause
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1. cirrohosis of the liver 2. hepatocellular carcinoma
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What are the symptoms of hapatisis C infection
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jaundice, extreme fatigue, abdominal pain, nausea and vomiting
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How is infection with viral hepatitis Dx'ed
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detection of virus specific antibodies and/or viral nucleic acid via PCR
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What family and genus does Hepatitis C belong to? What viral properties does it have?
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Family= flaviviridae, Genus= Hepacivirus properties= small, enveloped positive sense (messenger ready) RNA, infects only humans in nature
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T/F there is a vaccine for Hepatitis C
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false, also treatments are only 50% effective
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What factors exaplain our limited understanding of HCV pathogenesis
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recently discovered (1989), unable to culture until 2005, no small animal model (chimps only), very heterogenous in infected induvidual, long asymptomatic period
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How is HCV transmitted
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blood to blood contact
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Describe the typical outcomes for HCV infection
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75-85% develop chronic infection, 60-70% develop liver disease, 5-20% develop liver cirosis, 1-5% dies from cirrosis or carcinoma
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Describe the HCV replication cycle
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1.Attachement via receptor mediate endocytosis, E1 and E2 envelope proteins 2. Release of viral genome upon endosome acidification 3. translation of viral mRNA using IRES giving rise to polyprotein that is later cleaved 4.Viral genome repliaction at the host cell ER membrane 5. assembly of new virus 6. Exit from the cell via budding, hitching a riding on host secretory pathways
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Describe the HCV genome including the non-coding and coding regions
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positive sense ssRNA, non-coding sequences contain a 5' IRES that directs cap independent translation, 3' X region is important for replication of viral RNA coding regions- struction proteins encoded at the 5' end and non structural at the 3' end, translated a a single, long polyprotein
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Describe the cleavage of the HCV polyprotein
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The poly protein is cleaved to give rise to 10 viral proteins. There are two types of proteases involed 1. host proteases at the ER and 2. Viral proteases N2/3 and NS3/4A
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What is the function of the HCV core protein
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formation of the viral capsid, inhibtionof IFN signaling and apoptosis
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In which two ways can HCV evade the afferent innate immune response
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1. Inhibition of TLR receptor pathways 2. Inhibition of RIG 1 like receptor pathways
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In which 3 ways can HCV evade the efferent innate immune response
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1. interferon pathway 2. PKR 3. 2',5' oligo A synthetase and RNAseL
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List the 3 keys to HCV's ability to establish a persistent infection
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1. infection is typically non-cytopathic, inhibition of apoptosis by viral core proteins and E2 proteins
2. Viral proteins inhibit many of components of the host immune response 3. HCV evades the adaptive immune response |
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How does HCV block TLR signaling pathways? (two ways)
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1. NS3/4A cleaves TRIF
2. NS5A sequesters MyD88 both of these mechanisms result in the inability of TLRs to signal transduce and activate interferon |
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How does HCV block RLR signaling pathways
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NS34/A cleaves MAVS which prevents the signal transduction required to activate interferon
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How does HCV block inteferon mediate signaling
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Core protein interfers with the STAT protein that is required to transduce the signal to upregulate interferon stimulated genes once interferon binds to the cell surface receptor
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How does HCV inhibit the effectors of the IFN mediate response?
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1. NS5A and E2 inhibit the phosphorylation of PKR (PKR must be phosphorylated in order to phosphorylated eLF2a and shut off protein synthesis) 2. NS5A inhibits 2'5, oligo A synthetase which is needed to turn on RNAse L, HCV also has RNAseL resistant sequences
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Clearance of HC infection correlates with…
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a robuts T cell response during acute infection
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How does HCV avoid the adapative immune response?
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CD8 T cells gradually become impaired in their ability to kill HC infected cells and secrete interferon-g, The mechanism is poorly understood but may be due to 1. poor response by CD4 helpers, 2. Regulatory T cells supressing the response in order to prevent excessive immune mediate tissue damage 4. energy require to maintain full blown response is too great
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What two feature of HCV may contribute to its ability to evade the adpative immuen response?
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1. High replication rate
2. Error prone polymerase (NS5B) combined these features give rise to a heterogenous virus population leading to quasi-speices, the imune reponse provides seletive pressure that favors continued propagation of viruses whose epitopes cannot be recognized/ neutralized |
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How does HCV cause liver disease
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1. Apoptosis of HCV infected cells (limited) 2. CTL medaited killing of infected cells 3. Death of non infected bystander cells repreated cycles of cell death and accumulation of scar tissue leads to cirrhosis and liver dysfunction
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How does HCV cause liver disease
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1. Apoptosis of HCV infected cells (limited) 2. CTL medaited killing of infected cells 3. Death of non infected bystander cells repreated cycles of cell death and accumulation of scar tissue leads to cirrhosis and liver dysfunction
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How does HCV cause liver cancer
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1. Production of nitric oxide and free radicals via the immune response leads to DNA damage 2. HCV mediated inhibtion of Rb and p53 prevents cell cycle arrest and apoptosis despite the presence of damaged DNA
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How does HCV inhibit Rb and p53
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HCV NS5B inhibits Rb, NS3 inhibits p53
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Describe the current drug therapy for treating HCV
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Pegylated INFa + ribavirin, the IFNa elicits an anti-viral state and the Ribavirin acts as a nuceloside analog (not a chain terminator) that incorporates into viral RNA inplace of A or G, the Tx is only 50% effective and there are numerous, severe side effects
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Telaprevir is a drug that is currently in clinical trials to treat HCV. It is an NS3/4A protease inhibitor. How would this drug be effective against HCV?
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NS3/4A is the HCV protease that is necessary for polyprotein cleavage and inhibition of TLR3 and RIG-1 siganling pathways
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define emerging disease
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newly discovered pathogen, spread of a pathogen into a new region, or change in pathogen resulting in widespread disease
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what are the three categories of important factors in disease emergence
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human, pathogen, environmen
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List some human factors that are important in disease emergence
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behavior, population density, poverty, war, immune status, farming and industry, medical practices, health infrastructure, etc.
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List some pathogen factors that are important in disease emergence
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mutation frequency, virulence, replication rate, transmission mechanism and efficiency, resistance, vectors and reserviors
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List some environmental factors that are important for disease emergence
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climate, natural disasters, eco-issues, animal/insect populations
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Describe the basic virology of west nile virus
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family flaviviridae, enveloped positive sense single stranded RNA
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Describe the WNV transmission cylce
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There is an enzootic cycle that rotates between mosquitoes and birds, dead end hosts include humans and horses
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How is WNV transmitted
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mosquito bites
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What are the sxs of WNV
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fever, fatigue, headahce, rash, neurologica abnormalities, muscle weakness, flaccid paralysis, 10% encepahlitic case fatalitiy rate
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What are the risk factors of WNV associated disease
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old, immunosupressed
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How was WNV most likely spread
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migratory birds
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Describe the basic virology of SARS
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family coronaviridae, enveloped, very large RNA genome, positive sense single stranded RNA, 3 distinct antigenic groups
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Where did the SARS outbreak originate
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Guangong province, Southern China
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Describe the origin of SARS
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initial conncetion with live animal marktes possible species jump from horseshoe bat or palm civet
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How do WNV and SARS differ in terms of type of emergence
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WNV spread to a naieve environment, SARS is a new pathogen
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How do WNV and SARS differ in terms of transmission
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WNV= mosquitoes, SARS= zoonotic, person to person
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How do WNV and SARS differ in terms of human factors
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WNV= movement of animals or cargo, mosquito habitat SARS= cultural food practices, movement of animals, travel
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How do WNV and SARS differ in terms of animal populations
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WNV= suceptible birds, migrations, SARS= suceptible animals
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How do WNV and SARS differ in terms of environment
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WNV= climate, SARS= habitate change??
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How do WNV and SARS differ in terms of pathogen factors
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WNV= adaptation to mosquitoes, SARS= adapation to animal hosts and humans
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Describe Kuru
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prion disease first identified in Papua New Guinea, connected to cannibalism especially in women that ate brain
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Describe the two isofomrs of a prion
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PrPc= found in all animals, function not well understood, suceptible to proteolysis, souble, mostly alpha helical , PrPsc=misfolded form of prion protein, resistant to proteolysis, insoluble, mostly beta sheet
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How do prions cause disease?
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misfolded proteions can induce misfolded state in host PrP, the misfolded Prp's aggregate and cause local damage to tissue through apoptosis of neurons, damage to nerve cells (because they
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How does sporadic CJD compare to Familial
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Sporatic CJD is caused by sporatic muations of the PrP gene the mean age of death is 68 years and the duration of illness is 4-5 months. Familial CJD is an autosomal dominant inheritance of the mutation in the PrP gene the age of onset is 35-60 years and it causes a permanent insomnia that leads to death in 7-18 monts
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what are the three types of CJD
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sportic -sporatic muation, familial- inherited mutation, variant-acquired by infection with misfolded PrP
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What are the two ways to aquire variant CJD
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1. iatrogenic 2. comsumption of tainted beef (UK)
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Describe the spread of Bovine spongiform encephalopathy that lead to the transmission of CJD in tainted beef
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cows were fed meat and bone meal made form other cows, transmitted prion
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Describe the genetic predisposition that lead to pathoglogy in induviduals that ate CJD tainted beef
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large majority of induviduals that died of CJD had a mutation in their native PrP possibly making their prions more suceptible to misfolidng
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How can prion diseases be prevented?
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Resistant to standard autoclave, heat, etc, need special sterilization practices, cullingof livestock heards, change in cultural practices (no cannibalism)
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Describe prion specificity
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only prions from certain species appear infectious, species specific prions had significant similarity at the sequence level to human PrP, belive to differn in beta sheet strcture
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What are some possible future treatments for prion diseases
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RNAi against native PrP protein, Antibody therapy against misfolded PrP, Quinacrine to prevent aggregates, molecules that stablize native PrP, big hurdle is crossing blood-brain barrier
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Is there a treatment for CJD?
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no 100% fatal
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What 4 families of viruses cause Hemorrhagic fever?
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1. Arenaviruses 2. Bunyaviruses 3. Filoviruses 4. Flaviviruses
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List some common features of hemorrhagic fever viruses
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1. all have non human endogenous hosts in which they usually do not cause severe disease 2. people are infected when they're in the wrong place at the wrong time 3. transmission from endogenous host to human invovles multiple routs 4. poor hospital practices in developing countries contribute to spread
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Describe the common features of hemorrhagic fevers
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severe, multip system syndromes, begin with fever, myalgia, headahce, prostration, rapid progression to capillary leakage, hypotension, systemic shock and death, frank hemorrhage is present in sever cases, wide and diffuse reflecting widepread vascular damage but not life threatening blood loss, death is due to hypotension and systemic shock
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List some key events in the pathogenesis of hemorrhagic fever viruses
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vascular damage to the endothelium, activation of cytokine storms and complement, activation of coagulation cascades, thrombocytopenia
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Describe the basic virology of arenaviruses
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ambisense RNA genome, envelopled
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List two hemorrhagic fevers that are caused by arena viruses
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South American HF and Lassa Fever
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Describe Lassa Fever Virus
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Endemic in West Africa, rodent to human transmission via urine, feces, and butchering, secondary human to human transmission with the potential for nosocomial outbreaks
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How can Lassa Fever virus be prevented
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village based programs for rodent control and avoidance, hospital training to avoid nosocomial spread, diagnostic technology transfer, specific antiviral chemotherapy (ribavirin)
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Where/ how did Filovirus- Marburg HF originate
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Marburn Germany in workers processing African Green Monkey kidneys for cell culture production
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Is there a treatment for CJD?
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no 100% fatal
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What 4 families of viruses cause Hemorrhagic fever?
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1. Arenaviruses 2. Bunyaviruses 3. Filoviruses 4. Flaviviruses
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List some common features of hemorrhagic fever viruses
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1. all have non human endogenous hosts in which they usually do not cause severe disease 2. people are infected when they're in the wrong place at the wrong time 3. transmission from endogenous host to human invovles multiple routs 4. poor hospital practices in developing countries contribute to spread
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Describe the common features of hemorrhagic fevers
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severe, multip system syndromes, begin with fever, myalgia, headahce, prostration, rapid progression to capillary leakage, hypotension, systemic shock and death, frank hemorrhage is present in sever cases, wide and diffuse reflecting widepread vascular damage but not life threatening blood loss, death is due to hypotension and systemic shock
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List some key events in the pathogenesis of hemorrhagic fever viruses
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vascular damage to the endothelium, activation of cytokine storms and complement, activation of coagulation cascades, thrombocytopenia
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Describe the basic virology of arenaviruses
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ambisense RNA genome, envelopled
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List two hemorrhagic fevers that are caused by arena viruses
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South American HF and Lassa Fever
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Describe Lassa Fever Virus
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Endemic in West Africa, rodent to human transmission via urine, feces, and butchering, secondary human to human transmission with the potential for nosocomial outbreaks
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How can Lassa Fever virus be prevented
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village based programs for rodent control and avoidance, hospital training to avoid nosocomial spread, diagnostic technology transfer, specific antiviral chemotherapy (ribavirin)
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Where/ how did Filovirus- Marburg HF originate
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Marburn Germany in workers processing African Green Monkey kidneys for cell culture production
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Describe the spread of Filoviruses (Ebola)
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acute infection, suspect index cases contracted virus from animal contact and goes to hospital where virus continues to spread
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Describe the sxs assocaited with Filoviruses (Ebola)
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abrupt onset of fever, headache myalgia and arthralgia, sore throat, weakness, followed by diarrhea, vomiting, stomach pain, rash, conjunctivitis, internal and external bleeding/ hemorrhaging
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Describe the clinical features of yellow fever
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ranges from limited febrile illness to severe hepatitis and hemorrhagic fever, pt appears to start to recover and then develops jandice, hypovolemic shock, acidosis, bleeding, hear, kidney, and liver failure
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How can yellow fever be treated and preventted
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no specific therapy, treat sxs, protect from mosquito exposure, there is a vaccine
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How can Dengue fever be treated and prevented
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no specific therapy or vaccine, treat for sxs, reduce breeding locations, spray pesticides, netting repellant etc
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List the 5 requirements of viral expression systems
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1. efficient dilivery of genes to be expressed into cells 2. promoter for gene expression must be strong and active 3. virus must stably accommodate foreign gene insert 4. proteins must be properly modified and biologicall active 5. system must be convenent and easy to use
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Describe how Baculovirus expression vectors are made
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use the promoter for the polyhedrin gene, the foregin gene for expression is inserted into the virus genome in place of the polyhedrin gene while maintaining the polyhedrin promoter, the exchange occurs about 10% of the time
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What are the advantages of using vaccinia virus vectors
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low pathogenicity, grows well in cell culture, easy to produce in stable form, elicits strong immune memory, limited side effects
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Describe how a vaccinia virus vector is generated
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Replace the tymidine kinase gene with gene of interest using homologous recombination. Wild type TK postive strains will die when drug selected with bromo-deoxyuridine. Transformed strains will survive.
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Define gene therapy
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the transient or stable introduction of a gene inot a cell tissue or individual for therapeutic purposes
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what is the "main theme" of gene therapy
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the use of virus vectors to deliver a gene to correct a genetic deficency or to kill unwanted cells
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What are the four requirements for gene therapy
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1. gene must be delivered to the proper target
2. protein must be produces at proper level for a sufficient length of time 3. Vector-transduced cell must be stable not removed by host immune response and not produce infectious virus 4. vector must not cause side effects |
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How might a gene for gene therapy be delivered?
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direct infusion, gene guns, ex vivo
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Describe the ex vivo approach to gene therapy
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Remove cells from an induvidual, transduce desired gene into those cells, return the genetically engineered cells to the patient
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Given some examples of the types of genes used for gene therapy
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antigens, cytokines, tumor supressors
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How might gene therapy be used for cancer treatment
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1. deliver a virus to kill tumor cells
2. Insert functional tumor supressor genes 3. Insert cytokine genes to improve immune function 4. Insert genes to increase chemotherapy effectivness 5. introduce suicide genes into tumor cells (convert non toxic drug into toxic substance) |
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What four properties must be considered when designing a viral vector
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1. type of target cell
2. poteintial for an immune response induced by the vector 3. length of time for required expression 4. ease of vector production |
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What is the general principle of viral vector design
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must engineer a virus that is replication defective but maintains its ability to attach and infect specific cells. Virus must express the transgene in a stable manner and cause a limited immune response
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Describe the negative outcome experienced by Jesse Gelsinger during the 1990 ADA gene therapy trial
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died from massive immune response to adenovirus vector
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In addition to acute immune responses to viral vectors what other risk do they present
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later onset of cancer due to insertional mutanagenesis
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what are some +/- to the use of plasmids as vectors for gene therapy
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-low transient expression, inefficient delivery
+minimal immune response, no integration of plasmid |
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What are some +/- to the use of retroviruses as vectors for gene therapy
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+good level of expression over long period, stable integration, will only transduce dividing cells
-insertional mutagenesis, require a helper cell line for packaging and delivery |
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What is the purpose of a helper cell line
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Helper cell lines are used in retrovirus gene therapy. They are cell lines that already express the gag, pol, and env genes that are are used to package the transgenic RNA. they are required because the retrovirus is replicaiton incompetent
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What are the +/- to the use of adenovirus as gene therapy vectors
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+ high transduction frequency in many cell types, vector DNA does not integrate, high expression (but short), easy to produce
-must use helper cell lines, contamination with wild type virus, expression of transgene is short lived, triggers a strong immune response |
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Viral vectors must be replication....
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incompetent
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